TDP-43 proteinopathy is a spectrum of neurodegenerative diseases characterized by the presence of TDP-43 positive inclusion bodies in the affected tissues. Alzheimer?s disease (AD), the most common form of dementia, is characterized clinically by cognitive impairment with memory loss and pathologically by beta-Amyloid plaques (Abeta), tau neurofibrillary tangles (tau NFTs) and neurodegeneration. Approximately 50% of AD patient samples show TDP-43 positive pathology in addition to Abeta and tau NFTs. Furthermore, TDP-43 positive AD cases are 10 times more likely to show cognitive impairment, including dementia, compared to TDP-43 negative ones. Therefore, elucidating molecular mechanisms underlying TDP-43 induced neurodegeneraion will advance our understanding of the pathogenesis of AD, AD-related dementias, and related neurodegenerative diseases. It is well established that mitochondrial dysfunction contributes to AD pathogenesis. However, only recently has it been demonstrated that enhancing mitochondrial proteostasis reduces amyloid-? misfolding and neurotoxicity, providing a new avenue for therapeutic development in Alzheimer?s and AD-related dementias. Although it has been published that TDP-43 is partially localized in mitochondria and is associated with mitochondrial dysfunction, it remains unresolved whether mitochondria protect against or contribute to TDP-43 induced neurodegeneration, especially events critical for cognitive impairment. Thus, rigorous and systematic studies are necessary to define the role and underlying mechanisms of mitochondria in neurodegeneration associated with TDP-43. We have obtained exciting preliminary data that mitochondrial damage is not only the earliest detectable defect in cellular and animal models of TDP-43 proteinopathy but also a prominent feature in patient samples. Our data show that TDP-43 induces mitochondrial damage, disrupts mitochondrial proteostasis and activates the mitochondrial unfolded protein response (UPRmt). Importantly, enhancing mitochondrial quality control (MQC) not only reduces mitochondrial impairment, but also ameliorates TDP-43-induced neurodegeneration. We propose to take an integrated approach using molecular, biochemical and cell biological assays together with animal models, patient samples and patient iPSC-derived neurons to examine the role of mitochondria, especially mitoproteases and other MQC genes, in TDP-43-induced neurodegeneration. In Aim 1, we will determine the in vivo role of TDP-43 in disrupting mitoproteostasis and inducing UPRmt, and we will identify and characterize mitoproteases critical for clearance of misfolded TDP-43 protein in cultures and in vivo. In Aim 2, we will dissect mechanisms of TDP-43 degradation in mitochondria and TDP-43-induced neurodegeneration by examining interaction of TDP-43 with mitoproteases, impact of oxidative stress on TDP-43 protein misfolding/degradation and the function of the candidate mitoproteases in modulating MQC. In Aim 3, we will systematically examine mitochondrial impairment in patient samples and determine the role of MQC genes in the pathogenesis of TDP-43 proteinopathy using patient iPSC-derived neurons. If enhancement of mitochondrial proteostasis and MQC ameliorates TDP-43 induced mitochondrial damage and neurodegeneration in human neurons, it will establish a previously unknown role of mitoproteostasis in TDP-43 related neurodegeneration. Completion of our proposed work will help elucidate molecular mechanisms underlying AD, AD-related dementias and other disorders with TDP-43 pathology. This study will also identify potential therapeutic targets to improve clinical outcomes of these devastating neurodegenerative diseases.